I. Field of the Invention
The present invention relates to the general fields of biochemistry, oncology, computational bioengineering/bioinformatics, structural biology/molecular biophysics, medicinal chemistry, pharmacology, X-ray crystallography, cellular biology, and/or molecular imaging. More particularly, the compositions and methods of the invention relate to the optimization of various parental drugs and the design of a wrapping optimized drug (“wrapper compound”) using complementation of packing defects in a drug target.
II. Background
Molecularly targeted therapy and diagnosis are powerful tools in the fight against cancer. In this regard, signal-transducing molecules, the kinases, have become quintessential drug targets. However, the evolutionary relatedness of kinases makes most inhibitory drugs cross reactive, with a high likelihood of off-target associations, yielding highly uncertain and often dangerous results. The most alarming aspect of such treatments is the actual unpredictability in the extent of specificity, including the associated health-related risks and side-effect complications.
Ligand cross reactivity, amply illustrated by drug-based kinase inhibition, has been identified as a major cause of side effects and of misleading or ambiguous diagnosis. Additional methods are needed that use molecular design to modulate cross reactivity within the oncokinome to sharpen the specificity of a new generation of drugs on clinically relevant targets for therapeutic and imaging purposes. (A kinome is a subset of the genome consisting of the protein kinase genes and an oncokinome is a subset of kinome that is associated with or related to cancers.) This is a challenging problem since the extent of structural conservation of kinases, especially at the primary (ATP-) binding sites, is staggering. The starting point is the observation that there is a molecular marker for ligand specificity so far overlooked, i.e., the packing defects that are not conserved across evolutionary related proteins (Fernandez and Berry, 2004). Packing defects are functionally critical because they are indicators of protein interactivity, or markers for protein-ligand association (Fernandez and Scheraga, 2003; Fernandez, 2004) and constitute a decisive factor in macromolecular recognition (Ma et al., 2003; Deremble and Lavery, 2005). These defects consist of intramolecular hydrogen bonds incompletely packed, or poorly protected from water attack. They are termed dehydrons (Fernandez, 2004; Fernandez and Scott, 2003 a,b), because they promote their own dehydration as a means to strengthen and stabilize the electrostatic interaction. Dehydrons may be identified from protein structure by quantifying the extent of intramolecular desolvation of the hydrogen bonds. This parameter indicates the number of “wrapping” nonpolar groups within a microenvironment around the hydrogen bond. Thus, there is a need to engineer drugs that “wrap” packing defects that are not conserved across paralogs.
Thus, additional compositions and methods are needed to solve this critical biomedical problem and create a translational platform to promote target specificity in drug development and drug-based imaging diagnosis.